PROJECT SUMMARY/ABSTRACT The somatic cells remain quiescent upon terminal differentiation. Perturbation of this process can lead to cell quiescence exit and proliferation, which is implicated in cancer and tissue regeneration. The dimerization partner, RB-like, E2F, and multi-vulval class B (DREAM) complex, also called the DRM complex in Caenorhabditis elegans and dREAM complex in Drosophila melanogaster, is an evolutionarily conserved cell cycle-regulatory multiprotein complex. In association with co-activators and co-repressors, the DREAM complex directly modulates the expression of various genes directly related to cell cycle and cell quiescence. However, it is unknown how the DREAM complex is regulated in the physiological and pathological conditions. Proliferating cell nuclear antigen (PCNA)-associated factor (PAF; also known as PCLAF/KIAA0101) is highly upregulated in many cancers but barely expressed in normal cells. Our comprehensive approaches, including molecular and cellular biology, mouse genetics, proteomics, and transcriptomics, found that PAF is indispensable for cell quiescence exit and cell proliferation possibly by remodeling the DREAM complex. Based on our previous studies and preliminary results, we hypothesize that PAF remodels the repressive DREAM for cell quiescence exit and proliferation for the maintenance and activation of cell stemness in lung cancer and lung tissue regeneration. This central hypothesis will be tested by pursuing two specific aims: Aim 1) Decipher the molecular mechanism of the PAF-remodeled DREAM complex; Aim 2) Determine the pathological and physiological roles of PAF and PAF-expressing cells in lung cancer and tissue regeneration. The proposed study will address how PAF remodels the DREAM complex for bypassing the cell quiescence and accelerating cell proliferation. Similarly, how stem and facultative progenitor cells become active/mitotic for tissue regenerating will be addressed by testing the working model - ?PAF-remodeled DRAEM complex induces the cell cycle re-entry of the stem and progenitor cells upon tissue injury?. This study will establish a new paradigm in lung cancer initiation and regeneration by revealing how the remodeling of the DREAM complex contributes to pathological (cancer) and physiological (regeneration) processes. Moreover, the completion of this study may propose the PAF-DREAM axis as a targetable vulnerability of lung cancer.